U.S. patent number 4,610,687 [Application Number 06/638,044] was granted by the patent office on 1986-09-09 for method for breeding control in female bovines.
This patent grant is currently assigned to Board of Trustees Operating Michigan State University. Invention is credited to Ralph L. Fogwell.
United States Patent |
4,610,687 |
Fogwell |
September 9, 1986 |
Method for breeding control in female bovines
Abstract
A method for reducing the time to estrus onset and duration of
estrus in female bovines, is described. The method involves a
sustained low level release of progestin over time with injection
of a luteolytic agent, particularly a prostaglandin, towards the
end of the time such that there is an overlap of progestin and
prostaglandin administration. The sustained release is preferably
by means of a vaginal implant. The method is faster and easier to
use than prior art methods.
Inventors: |
Fogwell; Ralph L. (Bath,
MI) |
Assignee: |
Board of Trustees Operating
Michigan State University (East Lansing, MI)
|
Family
ID: |
24558410 |
Appl.
No.: |
06/638,044 |
Filed: |
August 6, 1984 |
Current U.S.
Class: |
424/433; 514/169;
514/170; 514/173; 514/841; 604/515 |
Current CPC
Class: |
A61K
9/0024 (20130101); A61K 31/557 (20130101); Y10S
514/841 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61K 31/557 (20060101); A61K
009/22 (); A61K 031/557 () |
Field of
Search: |
;514/173,170,169,841
;604/890,891 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Griffin; Ronald W.
Attorney, Agent or Firm: McLeod; Ian C.
Claims
I claim:
1. A method for fertile breeding control in female bovines
comprising:
(a) establishing an estrus and ovulation blocking period of several
days by continuous administrating of a progestin using an implant
which slowly releases the progestin into the blood stream;
(b) injecting a luteolytic agent while continuing the
administration of the progestin for a period of 1 to 6 days;
and
(c) terminating the administration of the progestin, thereby
allowing estrus and ovulation to occur in a shorter time period and
in a relatively narrower time span than if administration of the
progestin was terminated at the time of injection of the luteolytic
agent.
2. The method of claim 1 wherein the progestin is progesterone.
3. The method of claim 2 wherein the progesterone is naturally
occurring.
4. The method of claim 2 wherein the progesterone in the blood
stream during and after injecting the luteolytic agent is between 1
to 2 nanograms per ml for at least about 1 day.
5. The method of claim 1 wherein the luteolytic agent is a
prostaglandin.
6. The method of claim 5 wherein the prostaglandin is PGF.sub.2
alpha.
7. The method of claim 1 wherein the progestin is released by means
of a vaginal implant which provides a timed release of the
progestin over a period of at least about 5 days prior to injecting
the luteolytic agent.
8. The method of claim 1 wherein the implant is a vaginal implant
which contains between about 0.5 and 2% by weight progesterone in
timed release composition as the progestin and wherein the
luteolytic agent is PGF.sub.2 alpha which is injected in an amount
of between about 20 and 30 mg into the blood stream of the
bovine.
9. The method of claim 8 wherein the progesterone is about 2% by
weight of the implant and the luteolytic agent is about 25 mg.
10. The method of claim 1 wherein progesterone as the progestin is
continuously administered for about six (6) days, prostaglandin as
the luteolytic agent is injected on the sixth day, the progestin
administration is continued for three (3) more days and then the
administration of progestin is terminated, thereby allowing estrus
and ovulation to occur.
Description
BACKGROUND OF THE INVENTION
(1) Field of the Invention
The present invention relates to a method of fertile breeding
control in female bovines by means of overlapping dosages of a
progestin and a luteolytic agent using an implant for releasing low
levels of the progestin over a time period into the blood stream
and injection of the luteolytic agent towards the end of the period
so that the progestin and agent are being administered together. In
particular the present invention relates to the use of a vaginal
implant for releasing the progestin over a period of time into the
blood stream.
(2) Prior Art
Success of detecting cows in estrus averages 50 percent but 85 to
100 percent is possible. High success in detecting estrus requires
at least four 30 minute periods of observation or 2 hours per day.
Thus, low success of detecting estrus is due largely to inadequate
observations of cows because labor is expensive and/or not
available. Failure to observe for or detect estrus limits use and
success of artificial insemination (AI). Presently AI is used on
about 75 percent of dairy cattle and about 5 percent of beef
cattle. Development of methods to predict estrus or ovulation would
not be fruitful since this approach only addresses one animal and
requires labor and management. In addition, no profound biological
parameter has been identified to form a basis for a "cow-side" test
of estrus/ovulation.
Methods exists to control when estrus and/or ovulation occur.
Commercially available methods include:
a. Syncro-Mate B.RTM. from CEVA (a French company)
b. Prostaglandin F.sub.2 alpha and analogs
(1) Lutalyse.RTM. from Upjohn
(2) Estrumate.RTM. from Haver Lockhardt
(3) Syncro-Cept.RTM. from Diamond Labs.
The value of the present methods (listed above) to control estrus
and/or ovulation is realized primarily through improved success of
detecting estrus. However the ultimate goal of controlling
ovulation is for AI to occur at a prescribed time after application
of agents to control ovulation (AI by appointment) without regard
for estrus. Acceptable results with "AI by appointment" will only
be realized if all cattle in a group ovulate within a range of 24
hours. Present methods to control ovulation do not cause sufficient
precision to warrant AI by appointment. For example, with
prostaglandins, the range for occurrence of estrus or ovulation is
4 to 5 days. With Syncro-Mate B the range is 3 to 4 days. In
addition to variation among individuals within a group, average
intervals to estrus or ovulation are highly variable among groups
of cattle, particularly when using prostaglandin.
U.S. Pat. No. 3,892,855 to Short describes the closest known prior
art which uses a progestin and a luteolytic agent. In the method
described in this patent, a subcutaneous progestin implant is
removed at the time of injection of the luteolytic agent. The
result is the onset of estrus and ovulation over a period of 1 to 5
days which is a wide time span. Further subcutaneous implants
produce a risk of infection.
OBJECTS
It is therefore an object of the present invention to provide a
method whereby the time interval or span of estrus is reduced to
about 24 hours from about 40 hours and whereby the onset of estrus
is reduced by about one-half over that obtained by termination of
progestin and injection of luteolytic agent. Further it is an
object of the present invention to provide a preferred method which
uses a vaginal implant rather than a subcutaneous implant. Further
still it is an object of the present invention to provide a method
which is relatively more precise and simpler to perform than the
prior art method. These and other objects will become increasingly
apparent by reference to the following description and the
drawings.
In the Drawings
FIG. 1 is a graph showing a hormonal profile for the method of the
present invention.
FIG. 2 is a chart showing the steps in the method of the present
invention.
FIG. 3 is a graph showing control and method (experimental) estrus
onset after removal of an implant for progesterone.
FIG. 4 is a graph showing peaks of luteinizing hormone (LH).
GENERAL DESCRIPTION
The present invention relates to a method for fertile breeding
control in female bovine comprising:
(a) establishing an estrus and ovulation blocking period of several
days by continuous administering a progestin using an implant which
slowly releases the progestin into the blood stream;
(b) injecting a luteolytic agent while continuing the
administration of the progestin for a period of several days;
and
(c) terminating the administration of the progestin, thereby
allowing estrus and ovulation to occur in a shorter period of time
and in a relatively narrower time span than if administration of
the progestin was terminated at the time of injection of the
luteolytic agent. A vaginal implant is preferred because there is a
more precise control over the timed release of the progestin and
avoidance of infection.
SPECIFIC DESCRIPTION
The major source of variation in control of estrus/ovulation
appears to be functional status of ovarian follicles. The principle
of the method of the present invention is that cattle with large
estrogen-producing (estrogen-active) follicles will experience
estrus/ovulation sooner than cattle without estrogen-active
follicles. The key to precise regulation of ovulation is to
establish homogeneous follicular status (e.g. estrogen-active)
among all individuals in a group of cattle.
The rationale for our approach to control status of follicles
evolves from several concepts established in the literature.
a. Progesterone exerts potent negative feedback control on
secretion of luteinizing hormone (LH). Within limits, this negative
modulation of LH is related to dose of progesterone.
b. Growth and function of antral ovarian follicles is dependent on
concentrations of LH and follicle stimulating hormone (FSH).
Our approach to precise regulation of ovulation in cattle consists
of three parts: (1) exogenous progesterone to block occurrence of
estrus/ovulation during the period of treatment, (2) a luteolytic
agent to remove functional corpora lutea and (3) concentrations of
progesterone for several days after the injection of the luteolytic
agent that are low enough to allow for increased secretion of LH
but no preovulatory surges of LH. These features are illustrated in
FIG. 1. The preferred method to deliver progesterone is a
Progesterone Releasing Intravaginal Device (PRID). This device is a
coiled stainless steel strip coated with a silicone rubber
(Silastic.TM. Dow) impregnated with progesterone in an amount of 2%
progesterone based upon the weight of silicone rubber. Any other
timed release composition can be used as is well known to those
skilled in the art.
The key is that release of progesterone results in precise
concentrations of progesterone in serum so that basal secretion of
LH increases which promotes growth of estrogen-active follicles.
However, no ovulations occur since preovulatory surges of LH are
blocked. Thus, when PRID's are removed, all animals experience
estrus, preovulatory surges of LH, and ovulation within narrow
range of time (e.g..ltoreq.24 hours).
Two experiments have been conducted and represent preliminary tests
of this approach. As these data are presented, heifers were treated
according to sequences illustrated in FIG. 2. In contrast to
experimental heifers PRID's were removed from Controls when
luteolytic agent (Lutalyse.RTM.) was injected. Thus, sustained
increased secretion of LH occurred in experimental heifers but not
in controls. In each instance the prostaglandin was injected into
the buttocks in a saline solution. Other carriers can be used.
In both experiments reported, PRID's were 2 percent progesterone.
In one experiment, we observed heifers for estrus for 30 minutes at
four hour intervals and onset of estrus was first observation of
standing to be mounted. Results from synchronizing heifers which
were at various stages of an estrus cycle when PRID installed are
presented in FIG. 3.
In a separate study we examined occurrence of preovulatory surges
of LH as in indicator of ovulation (FIG. 4). Jugular blood was
sampled every 2 or 4 hours for 96 hours after removal of PRID and
serum was assayed for LH. From these data we identified intervals
from removal of PRID to peak of preovulatory surges of LH. These
heifers were synchronized with prostaglandin F.sub.2 alpha before
installing PRID. Thus, stage of an estrus cycle was not as variable
in this study since all heifers were diestrus (FIG. 4). However,
various stages of diestrus existed.
RESULTS (Experiment I):
After removal of PRID, distribution of estrus (FIG. 3) for
experimental heifers was different from control heifers.
Specifically for experimental heifers relative to controls, more
were detected in estrus overall and more were detected in estrus
during an interval of 24 (.+-.12) hours surrounding the respective
means (FIG. 3). Therefore retention of PRID for 3 days after
injecting PGF.sub.2 alpha contributed to increased detection and
precision of estrus in heifers.
RESULTS (Experiment II)
After removal of PRID, distribution of peaks of LH surges (FIG. 4)
for experimental heifers was different from controls. Specifically,
100 percent of experimental heifers had peaks of LH surges within
an interval of 24 (.+-.12) hours of the mean for that group.
Therefore retention of PRID for 3 days after injecting PGF.sub.2
alpha increased precision of preovulatory surges of LH in
heifers.
CONCLUSION:
Given that greater than or equal to .gtoreq.95 percent of LH surges
or estrus occurred within an interval of 24 hours, maintenance of
low concentrations of progesterone after injecting PGF.sub.2 alpha
enhances feasibility of artificial insemination at fixed time
without regard for estrus.
The main objective of the method of the present invention is to
increase precision of synchronizing preovulatory surges of LH (Exp.
1) and onset of estrus (Exp. 2) with a hormonal milieu of reduced
progesterone and increased basal. In both experiments exogenous
progesterone was administered using progesterone releasing
intravaginal devices (PRID 2% Progesterone). In Exp 1, heifers
received PRID for 7 days after which they all were injected with 25
mg of PGF.sub.2 alpha. In one group (experimental, n=9) PRID's
remained in heifers for 3 days after PGF.sub.2 alpha. In the
controls (n=8), PRIDs were removed at the time of PGF.sub.2 alpha.
After PGF.sub.2 alpha, jugular blood was sampled every 4 hours for
96 hours, then every 2 hours for 72 hours and finally every 4 hours
for 36 hours. Intervals from removal of PRID to peak of LH surge
averaged 33.5.+-.1.9 hours with a range of 28 to 42 hours for
experimental heifers. For controls, intervals from removal of PRID
to peak LH surge averaged 64.2.+-.4.9 hours with a range of 40 to
82 hours. The intervals from removal of PRID to peak LH in
experimental group were less variable (P<0.025) than in
controls. In Exp. 2, heifers were assigned to experimental (n=44)
and control (n=23) groups. Schedule for PRID and PGF.sub.2 alpha
were as described in Exp. 1. After removal of PRID all heifers were
observed for estrus for 30 minutes every 4 hours for 96 hours.
Intervals from removal of PRID to onset of estrus (stood to be
mounted) averaged 39.5.+-.1.4 hours with a range of 24 to 56 hours
for experimental heifers. For controls, intervals from removal of
PRID to onset of estrus averaged 60.5.+-.2.8 hours with a range of
36 to 60 hours. The intervals from removal of PRID to onset of
estrus were less variable (P<0.025) for experimental than for
control heifers. Retention of PRIDs in heifers for 3 days after
PGF.sub.2 alpha increases synchrony of preovulatory surges of LH
and onset of estrus in heifers.
The method is thus particularly adapted for establishing the onset
of estrus in a herd or group of cattle. In general an amount of
progesterone above about 2% by weight of the PRID was not effective
and between 0.5 and 2% by weight was preferred. It was preferred to
inject between 20 and 30 mg of the luteolytic agent after a blood
level between about 1 to 2 nanograms of progesterone was reached.
Generally it required at least about 5 days in order for the
progesterone to be reduced to this level from an initially higher
level. The injection of the luteolytic agent was effective for 1 to
6 days with continued progesterone from the PRID before
removal.
* * * * *